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This report demonstrates that expression of the P140A O6-methylguanine DNA methyl transferase (MGMT) mutant via retrovirus-mediated gene transfer leads to significant, but modest, resistance of cells to both 6-benzylguanine (6-BG) depletion and treatment with 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU). Expression of the P140A/G156A double mutant appeared to be associated with reduced or unstable protein in hematopoietic cells. [ABSTRACT FROM AUTHOR]

Importance: Comatose survivors of out-of-hospital cardiac arrest experience high rates of death and severe neurologic injury. Current guidelines recommend targeted temperature management at 32 °C to 36 °C for 24 hours. However, small studies suggest a potential benefit of targeting lower body temperatures., Objective: To determine whether moderate hypothermia (31 °C), compared with mild hypothermia (34 °C), improves clinical outcomes in comatose survivors of out-of-hospital cardiac arrest., Design, Setting, and Participants: Single-center, double-blind, randomized, clinical superiority trial carried out in a tertiary cardiac care center in eastern Ontario, Canada. A total of 389 patients with out-of-hospital cardiac arrest were enrolled between August 4, 2013, and March 20, 2020, with final follow-up on October 15, 2020., Interventions: Patients were randomly assigned to temperature management with a target body temperature of 31 °C (n = 193) or 34 °C (n = 196) for a period of 24 hours., Main Outcomes and Measures: The primary outcome was all-cause mortality or poor neurologic outcome at 180 days. Neurologic outcome was assessed using the Disability Rating Scale, with poor neurologic outcome defined as a score greater than 5 (range, 0-29, with 29 being the worst outcome [vegetative state]). There were 19 secondary outcomes, including mortality at 180 days and length of stay in the intensive care unit., Results: Among 367 patients included in the primary analysis (mean age, 61 years; 69 women [19%]), 366 (99.7%) completed the trial. The primary outcome occurred in 89 of 184 patients (48.4%) in the 31 °C group and in 83 of 183 patients (45.4%) in the 34 °C group (risk difference, 3.0% [95% CI, 7.2%-13.2%]; relative risk, 1.07 [95% CI, 0.86-1.33]; P = .56). Of the 19 secondary outcomes, 18 were not statistically significant. Mortality at 180 days was 43.5% and 41.0% in patients treated with a target temperature of 31 °C and 34 °C, respectively (P = .63). The median length of stay in the intensive care unit was longer in the 31 °C group (10 vs 7 days; P = .004). Among adverse events in the 31 °C group vs the 34 °C group, deep vein thrombosis occurred in 11.4% vs 10.9% and thrombus in the inferior vena cava occurred in 3.8% and 7.7%, respectively., Conclusions and Relevance: In comatose survivors of out-of-hospital cardiac arrest, a target temperature of 31 °C did not significantly reduce the rate of death or poor neurologic outcome at 180 days compared with a target temperature of 34 °C. However, the study may have been underpowered to detect a clinically important difference., Trial Registration: ClinicalTrials.gov Identifier: NCT02011568.

Background: We evaluated the performance of stress imaging with technetium-99m-labeled tetrofosmin single-photon emission computed tomography (SPECT) and rubidium-82 positron emission tomography (PET) in patients with extreme obesity, defined as body mass index ≥40 kg/m 2 ., Methods: We identified patients with extreme obesity who underwent angiography in our center and either stress SPECT or PET within the previous six months. Cohorts of patients with extreme obesity and a <5% pretest likelihood of CAD who underwent SPECT (N = 25) or PET (N = 25) were also included., Results: In total, 108 patients who underwent SPECT (N = 57) or PET (N = 51) were identified. Scan interpretation was classified as definitely normal or abnormal in 83.3% of PET and 60.5% of SPECT scans, respectively (P < .01). PET demonstrated higher diagnostic accuracy and normalcy rate. PET was found to have higher specificity for the pooled cohort. Similar findings were observed using stenosis cut-offs of ≥50% and ≥70%., Conclusions: In patients with extreme obesity, PET enabled more definitive scan interpretation with less artifact compared to SPECT. PET provided higher diagnostic accuracy and specificity in the detection of obstructive coronary artery disease.

Ticagrelor has been endorsed by guidelines as the P2Y 12 inhibitor of choice in patients with acute coronary syndrome. Clinically, some patients on ticagrelor will require a switch to clopidogrel; however, the optimal strategy and pharmacodynamics effects of switching remain unknown. Patients with an indication to switch were randomly assigned to either a bolus arm (Clopidogrel 600 mg bolus followed by 75 mg daily, n=30) or a no-bolus arm (Clopidogrel 75 mg daily, n=30). Blood samples were collected at baseline, 12, 24, 48, 54, 60 and 72 hours (h) for assessment of platelet reactivity. The primary outcome was P2Y 12 reactivity units (PRU) at 72 h. Secondary outcomes included: PRUs at each time point, incidence of high on-treatment platelet reactivity (HPR), major adverse cardiac events (MACE) and TIMI bleeding at 30 days. Serial PRUs increased after switching to clopidogrel in both groups. At 72 h, no difference in PRU was observed (165.8 ± 71.0 vs 184.1 ± 67.7, bolus vs no bolus, respectively, p=0.19). At 48 h the PRUs were significantly lower in the bolus arm (114 ± 73.1 vs 165.1 ± 70.5, respectively; p=0.0076) and at 72 h, there was a significant reduction in incidence of HPR (26.7 % vs 56.7 %, p=0.02). No differences in MACE or TIMI bleeding were observed. Although a bolus strategy was not associated with improved platelet inhibition at 72 h; at 48 h, platelet inhibition was superior with reduced incidence of HPR. Larger studies will be required to determine its clinical significance. Until then, decision for giving a bolus of clopidogrel at the time of a switch may in part be dependent on the indication for switching, especially if there are concerns for bleeding risk.

Background/objectives: Individuals with extreme obesity (EO), defined by a body mass index (BMI) ≥ 40 kg/m(2), constitute an increasingly prevalent population at higher risk of procedural complications. The implications of increasing weight burdens among this subset of patients in the setting of elective coronary revascularization have yet to be adequately studied., Methods: We sought to define major complications in this group at one year following contemporary revascularization strategies by retrospectively analysing a cohort of consecutive EO patients undergoing elective percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG). The primary endpoint was a composite of peri- and post-procedural complications. Secondary endpoints included a cardiovascular composite and target vessel revascularization (TVR)., Results: Adjusted event-free survival curves for the primary endpoint among 133 patients differed significantly with higher BMI (>43.2 kg/m(2)) associated with greater risk (p=0.02). The primary endpoint occurred more frequently with CABG compared to PCI (24.2% vs. 5.0%, p < 0.01), which remained significant after adjusting for differences in baseline variables. Rates of the cardiovascular composite and TVR were comparable., Conclusions: Increasing BMI was associated with greater risk for major complications among EO patients undergoing elective coronary revascularization. PCI was associated with fewer complications; however, both revascularization strategies demonstrated equivalent rates of death, MI, and/or stroke. Larger studies may permit a better understanding of the associations between increasing BMI and specific outcomes and to evaluate the role for pre-procedural weight loss in this select population., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Anthracyclines, a standard component of induction therapy for acute myeloid leukemia (AML) are known to be cardiotoxic. Existing evidence supporting routine baseline pre-induction cardiac function testing is limited. We conducted a retrospective analysis of 119 consecutive patients diagnosed with AML at our center from 2009 to 2012. In the 76 patients for whom induction chemotherapy was planned, baseline ejection fraction measurements were rarely abnormal (four cases), and in none of these abnormal cases did the result change management decisions. Awaiting LVEF evaluation results led to a delay in chemotherapy administration by a mean of approximately 2 days at significant additional costs to the healthcare system. Routine baseline ejection fraction measurement should be abandoned as it does not change management, results in treatment delay and unnecessary healthcare expenditures. More selective baseline testing, preferentially in patients in whom there is a clinical reason of cardiac disease, should be pursued.

Background: Therapeutic hypothermia improves neurologic outcome and survival in patients following out-of-hospital cardiac arrest (OHCA). Endovascular cooling devices are commonly used to rapidly achieve and maintain hypothermia. The use of these devices may be associated with catheter related thrombosis. The objective of this study was to determine the risk of catheter related thrombosis associated with the use of an endovascular cooling catheter in patients referred for therapeutic hypothermia following OHCA., Methods and Results: We conducted a retrospective cohort study on consecutive patients, referred for therapeutic hypothermia following OHCA, between February 2012 and May 2013. Of 80 patients initially treated with therapeutic hypothermia, 61 completed the cooling protocol using an endovascular cooling device. The primary outcome was catheter related thrombosis defined as evidence of thrombus in the inferior vena cava, deep vein thrombosis or pulmonary embolism during the index hospitalization. We further evaluated the incidence of the primary outcome between patients on dose adjusted intravenous unfractionated heparin compared to those on a subcutaneous prophylactic regimen alone. Catheter related thrombosis was observed in 9/61 (14.7%), with nine events in the prophylaxis group compared to none in the full dose unfractionated heparin group (22.0% vs. 0.0%, p=0.02)., Conclusions: The use of endovascular catheters for induction of therapeutic hypothermia is associated with a high rate of catheter related thrombosis. This risk appears to be abrogated with dose adjusted unfractionated heparin infusion., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: In patients undergoing primary percutaneous coronary intervention (PPCI) ticagrelor is superior to clopidogrel in reducing cardiovascular events. This study sought to evaluate the effect of clopidogrel pretreatment on the pharmacodynamics of ticagrelor in patients undergoing PPCI., Methods: We measured platelet reactivity using the VerifyNow P2Y12 assay at baseline, 1, 2, 4, 6, 12, 24, and 48 hours following ticagrelor bolus in patients previously loaded with clopidogrel (C+T) and in thienopyridine-naive patients (T) referred to our centre for PPCI., Results: In total, 52 consecutive eligible patients with ST-elevation myocardial infarction (STEMI) were enrolled (27 C+T and 25 T). Baseline characteristics and mean baseline platelet reactivity units (PRUs) were similar between the groups. The primary endpoint, the proportion of patients achieving a PRU<208 at 2 hours, was more frequently achieved in the C+T group compared to T treatment (76.0% vs 44.4%, p= 0.026). Notably, C+T therapy resulted in fewer patients with high platelet reactivity at 1 hour (56.0% vs. 14.8%), 4 hours (100.0% vs. 61.5%) and 6 hours (100.0% vs. 64%, p<0.01 for all comparisons). Furthermore, C+T therapy was associated with lower PRU values from 2 to 48 hours., Conclusions: In patients referred for PPCI, ticagrelor bolus following clopidogrel resulted in more rapid and profound platelet inhibition, demonstrating a positive pharmacodynamic interaction. Further study is needed to determine if this pharmacodynamic effect translates into reduced clinical events.

Purpose of Review: This review will provide an overview of recent advances in the management of acute decompensated heart failure, focusing on major publications from the past few years., Recent Findings: There have been several publications investigating different strategies in the management of acute decompensated heart failure. Trials have investigated the role of ultrafiltration, diuretic infusions and recombinant B-type natriuretic peptide for the treatment of these patients., Summary: In patients with acute decompensated heart failure, the use of ultrafiltration in place of diuretics, diuretic infusions, and B-type natriuretic peptide has not shown benefit in recent trials. Unfortunately, there have been no major advances in the management of patients with acute decompensated heart failure.

Numerous clinical trials have demonstrated early reductions in cardiovascular events occurring independently of the lipid-lowering effects of statins. These pleiotropic effects have been attributed to antiinflammatory properties, to atherosclerotic plaque stabilization, and more recently to mobilization of endothelial progenitor cells (EPCs). Our aim was to evaluate the evidence supporting statin-induced EPC mobilization in humans. We, therefore, performed a computerized literature search and systematic review of randomized trials to determine the effect of statin therapy and statin dosing on circulating EPC numbers. Our literature search identified 10 studies including 479 patients which met inclusion criteria with publication dates ranging from 2005 to 2011. Seven studies compared statin to nonstatin regimens whereas 3 studied low versus high-dose statin therapy. Reported increases in EPC number ranged from 25.8% to 223.5% with a median reported increase of 70.2% when compared to nonstatin regimens with 7 of 10 studies reporting significant increases. Considerable heterogeneity exists in regard to patient population, statin regimens, and the definition of an EPC within the identified studies. In conclusion, randomized studies in humans suggest that statin therapy mobilizes EPCs into the circulation. Larger randomized studies using uniform definitions are needed to definitively establish this effect.

Background: Therapeutic hypothermia (TH) is associated with improved neurologic outcomes in comatose survivors of out-of-hospital cardiac arrest (OHCA). There are currently limited data on the outcomes of patients presenting with resuscitated OHCA in the setting of ST-segment elevation myocardial infarction (STEMI). We conducted a retrospective study to determine the outcomes of patients treated with TH for OHCA in a large regionalized STEMI program., Methods: Patients referred for primary PCI and TH between July 2004 and April 2011 were identified from the University of Ottawa Heart Institute STEMI database. The primary endpoint was survival to hospital discharge with sufficient neurologic recovery to enable discharge home., Results: Among 2467 consecutive patients referred for primary PCI, we identified 50 patients treated with TH following OHCA. Forty-nine underwent PCI, of which 47 (96%) received a stent. Median door-to-balloon time was 113min (IQR 91-151). Patients with good neurologic recovery were younger, mean 51 ± 9 years versus 64 ± 12, p<0.001, and had higher baseline creatinine clearance, 70 ± 19 mL/min/1.73 m(2) versus 53 ± 23 mL/min/1.73 m(2), p=0.007. The primary endpoint of survival with sufficient neurologic recovery to enable discharge home was reached in 30 patients (60%). Four survivors required levels of assistance that precluded discharge home., Conclusions: Therapeutic hypothermia in conjunction with primary PCI is associated with a favorable neurologic outcome in the majority of STEMI patients surviving OHCA. Our results suggest that TH is an important adjunctive therapy for STEMI patients suffering OHCA., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Cranial radiation therapy (CRT) is associated with neurocognitive morbidity in survivors of childhood acute lymphoblastic leukemia (ALL). For most patients, CRT has been replaced with intensified systemic and intrathecal chemotherapy, often including methotrexate (MTX). The impact of chemotherapy-only protocols on neurocognitive outcomes is unclear, and the importance of systemic MTX dose has not been established., Patients and Methods: Seventy nine of 120 eligible children diagnosed with high-risk ALL between the ages of 1.0 and 4.9 years participated in this retrospective cohort study. All patients were treated on a uniform chemotherapy protocol with one of three modalities of CNS prophylaxis, depending on their treatment era. In addition to intrathecal therapy, CNS-directed therapy consisted of CRT (18 Gy in 10 fractions) in 25 patients, high-dose intravenous (IV) MTX (8 g/m2 x 3 doses) in 32 patients and very high-dose IV MTX (33.6 g/m2 x 3 doses) in 22 patients. Participants completed tests of intelligence, academic achievement, attention, and memory., Results: Neurocognitive assessment was conducted at least 5 years after diagnosis (mean, 10.5 years, standard deviation, 2.7 years). No difference was detected on any neurocognitive measure between children treated with high-dose or very high-dose IV MTX. The combined MTX groups scored near the population mean on 17/18 measures. Children treated with CRT performed more poorly than the MTX group on most measures., Conclusion: Treatment strategies for young children with ALL that avoid CRT are associated with good long-term neurocognitive outcomes. In this cohort, the dose of IV MTX did not influence these outcomes.

Background: The merits of primary nephrectomy (PN) vs preoperative chemotherapy (PC) for patients with Wilms' tumor (WT) are much debated. Early data from the International Society of Pediatric Oncology suggested decreased intraoperative spillage but increased risk of local recurrence after PC. Patients with WT at our institution were managed with PC until 1996; subsequently, they underwent PN. This study compares these approaches as they affect tumor spillage, local recurrence, and survival., Methods: Patients with WT diagnosed at the Hospital for Sick Children from 1985 to 2003 were reviewed., Results: One hundred sixty patients were identified (114 PC and 46 PN). Tumor spill occurred in 6 (5.3%) of 114 PC and 2 (4.3%) of 46 PN patients. Tumor inhomogeneity, tumor size, and inferior vena cava compression/clot at diagnosis did not affect incidence of spill. Of 6 PC patients with surgical spill, 1 (17%) had significant tumor shrinkage, compared with 87 (81%) of 108 without spill (P < .001). Preoperative chemotherapy and PN had equal rates of surgical complications. Preoperative chemotherapy resulted in 12 (10.5%) of 114 local recurrences vs 5 (10.8%) of 46 with PN. Event-free survival and overall survival were 80% and 92% for PC at 129 months vs 85% and 96% for PN at 61 months., Conclusions: Preoperative chemotherapy and PN are equally effective in the treatment of WT with no difference in tumor spillage. Failure of the tumor to shrink in size with PC was significantly associated with an increase in tumor spillage and would suggest that a more cautious surgical approach be undertaken in these cases.

Cisplatin is an important chemotherapeutic agent in the treatment of many pediatric malignancies, but its use is limited in part by ototoxicity. The authors' institution has been administering standard-dose cisplatin by continuous infusion rather than bolus administration in germ cell tumors. The authors retrospectively reviewed 39 patients with germ cell tumors requiring chemotherapy over the past 20 years and recorded data including demographics, cumulative cisplatin dose, degree of ototoxicity (by the Brock grading system), and disease outcome. The median age was 9.4 years and the majority of children (48.7%) had endodermal sinus tumor. Twenty-one children received 400 mg/m of cisplatin or more. One child had evidence of significant ototoxicity at last follow-up (6.64 years after diagnosis). This patient received a total cumulative dose of 500 mg/m of cisplatin. Eighty-two percent of children achieved clinical remission of their disease. The authors conclude that continuous administration of cisplatin is associated with minimal ototoxicity while maintaining good tumoricidal efficacy, and further studies using this regimen are warranted.

Significant numbers of therapeutic abortions are performed for radiation-exposed pregnant women because of concerns about the teratogenic risk. However, available data suggest that current diagnostic radiation procedures are not teratogenic.

Background: Prophylactic use of cranial radiation therapy (CRT) in young children with acute lymphoblastic leukemia (ALL) is associated with significant long-term morbidity. Therefore, current treatment protocols for pediatric B-precursor ALL have abandoned prophylactic CRT in favor of intrathecal chemotherapy, combined with either high-dose methotrexate infusions (HD-MTX) or intensive systemic chemotherapy. In contrast, prophylactic CRT continues to be used in children with T-lineage ALL (T-ALL), who historically have had an inferior prognosis. We conducted a retrospective cohort study to determine the effect on survival of substituting HD-MTX for CRT in young children with T-ALL, a group that faces a high risk of long-term sequelae from CRT., Procedure: Twenty-six children, diagnosed with T-ALL between the ages of 1 and 5 years, were treated on the same high-risk leukemia protocol. Central nervous system (CNS) directed therapy consisted of either CRT (1,800 cGy) or HD-MTX (three doses of 8 g/m2), depending on the treatment era in which patients were diagnosed., Results: Of the 24 patients who entered remission, 12 received CRT and 12 received HD-MTX. Five-year event-free survival (EFS) (+/-SE) was 92 +/- 8% in the HD-MTX group versus 75 +/- 13% in the CRT group (P=0.23). Five-year overall survival (OS) was 100% in the HD-MTX group versus 75 +/- 13% in the CRT group (P=0.07). There were no CNS recurrences in the HD-MTX group. One patient treated with CRT developed a brain tumor., Conclusions: The use of HD-MTX instead of CRT as CNS-directed therapy in very young children with T-ALL does not compromise survival, while avoiding the adverse long-term effects of cranial irradiation., (Copyright 2003 Wiley-Liss, Inc.)